Cessation of Tyrosine Kinase Inhibitors in Patients With Chronic-phase Chronic Myelogenous Leukaemia

Leukemia, Myelogenous, Chronic Phase Clinical Trial

Official title:

Cessation of Tyrosine Kinase Inhibitors in Patients With Chronic-phase Chronic Myelogenous Leukaemia Who Achieve Stable Deep Molecular Response

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03131986
• Other study ID #: QMH-CML-001
• Status: Recruiting
• Start date: April 18, 2017
• Est. completion date: March 30, 2019

Study information

• Verified date: June 2018
• Source: The University of Hong Kong
• Contact: Yuk Man Cheung, MBBS(HK)
• Phone: 85222555161
• Email: drcarolcheung[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Since the debut of imatinib, the first tyrosine kinase inhibitor(TKI), more than two decades ago, the prognosis of patients with chronic myelogenous leukaemia (CML) has continued to improve. It has been shown that life expectancy of CML patients is approaching that of the general population nowadays. Currently, indefinite use of TKIs in patients with chronic-phase CML who achieve optimal response remains the standard practice. Nevertheless, the concepts of "treatment-free remission" and "functional" cure have been hotly discussed in recent years. A number of major international clinical trials have demonstrated that about 40-60% of CML patients who previously enjoyed deep molecular response on TKI manage to stay free from molecular relapse after cessation of TKI therapy.

Local experience of TKI cessation is lacking. This study aims to recruit patients diagnosed with CML, chronic phase who are treated with TKIs and remain in stable deep molecular response for at least two years. It is planned to stop TKI in these patients with regular monitoring, and determine their outcomes.

Description:

Major clinical trials including multicentre Stop Imatinib (STIM) trial, According to Stop Imatinib (A-STIM), TWISTER, Korean Imatinib Discontinuation Study (KIDS), European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI), and stop second generation (2G-TKI) showed that it is safe to stop TKI in patients who achieve stable deep molecular response (DMR) as defined by respective study groups. Around 40-60% of study participants managed to remain in treatment-free remission (TFR). For patients who experience molecular relapse after TKI withdrawal, most do so within the first 6 months. In addition, they all remained sensitive to TKI and majority of them were able to achieve the original molecular response. No loss of complete haematological response or progression to advanced phase CML was observed when the TKI was stopped.

Cessation of TKI in selected CML patients leads to freedom from treatment-related toxic effects. It is expected that at least 40% of enrolled patients will be in a sustained molecular remission after stopping TKI. Successful cessation would also reduce long-term treatment costs.

After cessation of TKI, fluctuation in molecular response, or even molecular relapse of the disease might bring about anxiety and distress in the patients. Some patients, estimated at around 40-60%, would experience molecular relapse and require resumption of TKI. Close molecular monitoring real-time polymerase chain reaction (RT-QPCR) after stopping TKI (every month in the first year and every 2 months in the second year) will allow early detection of possible molecular relapse and thus prompt resumption of TKI. Long-term risks of disease progression and drug resistance are uncertain, though the safety data from the TFR studies reported to date are sufficiently reassuring. Some patients might have musculoskeletal pain and pruritus after cessation of TKI, especially imatinib, which is also commonly known as "imatinib withdrawal syndrome".

Patients with chronic-phase CML who have been treated with a tyrosine kinase inhibitor for more than 3 years and had deep molecular response (breakpoint cluster region/Abelson murine leukemia (BCR-ABL1) transcript ≤0.0032% IS ratio, i.e. molecular response (MR4.5) for at least 2 years

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: March 30, 2019
• Est. primary completion date: March 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult (aged 18 years or above) patients diagnosed with chronic-phase CML

• In deep molecular response (i.e. MR4.5 or below, or those whose breakpoint cluster region -Abelson murine leukemia (BCR-ABL) transcripts were undetectable with at least 20,000 amplified copies of the control gene) for at least 2 years, confirmed by at least 3 data points with no more than one assessment between MR4 and MR4.5

• Under treatment with a TKI in first line, or in second line due to intolerance of another first-line TKI

• At least three years of treatment with the same TKI before enrolment

Exclusion Criteria:

• Under 18 years old

• Adults under law protection or without ability to consent

• Previous or planned autologous/allogeneic haematopoietic stem cell transplantation

• Documented kinase domain mutation

• History of disease progression (accelerated or blast phase)

• A change to the current TKI because of unsatisfactory response to a previous TKI in those who are on second line TKI (Note: patients are still considered eligible if the switch of TKI was due to intolerance or side effects)

• Patients who can speak neither Chinese nor English

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic Phase
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Chronic-Phase

Locations

Country	Name	City	State
Hong Kong	The University of Hong Kong	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
The University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

References & Publications (4)

Lee SE, Choi SY, Song HY, Kim SH, Choi MY, Park JS, Kim HJ, Kim SH, Zang DY, Oh S, Kim H, Do YR, Kwak JY, Kim JA, Kim DY, Mun YC, Lee WS, Chang MH, Park J, Kwon JH, Kim DW. Imatinib withdrawal syndrome and longer duration of imatinib have a close associat — View Citation

Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P; Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myel — View Citation

Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, Dang P, Goyne JM, Slader C, Filshie RJ, Mills AK, Melo JV, White DL, Grigg AP, Hughes TP. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residua — View Citation

Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, Gardembas M, Etienne G, Réa D, Roy L, Escoffre-Barbe M, Guerci-Bresler A, Tulliez M, Prost S, Spentchian M, Cayuela JM, Reiffers J, Chomel JC, Turhan A, Guilhot J, Guilhot F, Mahon — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	disease free survival	molecular relapse-free survival without treatment	12 months
Secondary	disease free survival	molecular relapse-free survival without treatment	24 months
Secondary	Overall survival	Overall survival without treatment	24 months